Involvement of cystatin C in immunity and apoptosis

Abstract

As an abundantly expressed cysteine protease inhibitor widely distributed in the organisms, cystatin C is involved in various physiological processes. Due to its relatively small molecular weight and easy detection, cystatin C is commonly used as a measure for glomerular filtration rate. In pathological conditions, however, growing evidences suggest that cystatin C is associated with various immune responses against either exogenous or endogenous antigens, which ultimately result in inflammatory autoimmune diseases or tumor development if not properly controlled. Thus the fluctuation of cystatin C levels might have more clinical implications than a reflection of kidney functions. Here, we summarize the latest development of studies on the pathophysiological functions of cystatin C, with focus on its immune regulatory roles at both cellular and molecular levels including antigen presentation, secretion of cytokines, synthesis of nitric oxide, as well as apoptosis. Finally, we discuss the clinical implications and therapeutic potentials of what this predominantly expressed protease inhibitor can bring to us.

Keywords: Apoptosis; Cystatin C; Cysteine proteases; Immune regulation; Inflammation.

Fig. 1

Cystatin C regulates immunity at cellular and molecular levels. Under pathological conditions, various stimuli cause variations in Cst C levels. Decreased Cst C up-regulates the activities of cathepsins, facilitating the cell matrix degradation, and IgG1 and IL-10 production to ensure a Th2-like response in favor of parasite proliferation. In addition, decreased Cst C promotes the interference of cathepsin with MHC-II loading in APCs to suppress host immunity against pathogen invasion. Increased or exogenously added Cst C in IFN-γ induced macrophages, on the other hand, down-regulates the cathepsin activities to increase IL-12, TNF-α, and NO generation that shift the immune responses towards protective Th1 immunity. Alternatively, Cst C can also disturb immmune homeostasis independent of cathepsins by antagonizing the binding of TGF-β to its receptor, or directly causing inflammation through formation of Cst C fibrils deposited in vascular walls. Cystatin C, Cst C; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; ROS, reactive oxygen species; IgG2, immunoglobulin G 2; TNF-α, tumor necrosis factor-α; NO, nitric oxide; IFN-γ, interferon-γ; TGF-β, transforming growth factor β.

Fig. 2

Dual effects of Cystatin C on apoptosis. On one hand, Cst C was reported to have anti-apoptotic effect via inhibiting Cat B-induced endonuclease activation for DNA fragmentation. In addition, Cst C can also inhibit Cat C-mediated Cat G leakage or pro-granzyme cleavage/activation to control apoptosis. On the other hand, induction of Cst C was found to decrease Bcl-2 expression and increase Bid protein to promote apoptosis through cyt c release from mitochondria. Moreover, Cst C was also reported to cause rapid de-granulation and granzyme activation in CTL for apoptosis via a perforin-dependent process. Cst C, cystatin C; Bcl-2, B-cell lymphoma-2; cyt c, cytochrome c;cat, cathepsin; CTL, cytotoxic T lymphocytes.